Radiofluorination of arenes, particularly non-activated or sterically hindered positions, with fluorine-18 remains a major challenge and a key limitation for the development of new radiotracers for in vivo imaging with positron emission tomography (PET) (see e.g., Miller et al., Angew. Chem. Int. Ed. 2008, 47:8998-9033).
Taking into consideration its convenient half-life (109.8 min), 18F is, with carbon-11, among the most desirable nuclides for small molecule PET radiotracers for imaging and quantification of biological processes, such as receptor expression and occupancy, metabolic activity, and cellular proliferation (see e.g., Ametamey et al., Chem. Rev. 2008, 108, 1501-1516).
Increased availability of cyclotron-produced (18O(p,n)18F) no-carrier-added [18F]fluoride for radiosynthesis has promoted the routine production of validated and target-selective PET radiopharmaceuticals suitable for pathology research, disease diagnosis, and drug development. Formation of 18F—Csp3 bonds using [18F]fluoride is generally much more facile than aryl radiofluorination, and can be achieved by nucleophilic displacement using primary or secondary alkyl electrophiles with [18F]fluoride. Nucleophilic aromatic substitution (SNAr) using nitroarene, aryl halide, or aryltrimethylammonium salt precursors is a pragmatic strategy for radiofluorination of activated (i.e., electron-deficient) arenes, but is of limited utility for non-activated or deactivated (i.e., electron-rich and/or sterically hindered) substrates. Similarly electrophilic radiofluorination using carrier-added [18F]F2 or the rarely utilized Balz-Schiemann and Wallach reactions using [18F]fluoride are incapable of producing structurally complex products in high specific activity.
A host of more selective radiofluorination methods for non-activated arenes has been developed with [18F]fluoride (see e.g., Brooks et al., Chem. Sci. 2014, 5:4545-4553; and Campbell et al., Chem. Rev. 2015, 115:612-633) including oxidative strategies (see e.g., Gao et al., Angew. Chem. Int. Ed. 2012, 51:6733-6737) and transition metal-mediated reactions (see e.g., Lee et al., Science. 2011, 334:639-642; Lee et al., J. Am. Chem. Soc. 2012, 134:17456-17458; Tredwell et al., Angew. Chem. Int. Ed. 2014, 53:7751-7755; Ichiishi et al., Org. Let. 2014, 16:3224-3227). While these methods have demonstrated innovative reactivity, aside from hypervalent iodonium-mediated methods, they have not been deployed in validated radiopharmaceutical syntheses for clinical imaging applications and appear to engender technical challenges that are preventing their routine use.
Hypervalent iodonium and sulfonium precursors offer metal-free radiofluorination with varying levels of reactivity and selectivity (see e.g., Pike et al., J. Chem. Soc. Chem. Commun., 1995, 2215-2216; Ross et al., J. Am. Chem. Soc., 2007, 129, 8018-8025; International Patent Application No. WO 2010/117435; Cardinale et al., RSCAdv., 2014, 4, 17293-17299; Rotstein et al., Nat. Commun., 2014, 5, 4365-4371; Mu et al., Eur. J. Org. Chem., 2012, 889-892; and Sander et al., Sci. Rep., 2015, 5, 9941-9945). Of these, diaryl iodonium salt precursors have been the most well-established alternative to SNAr in the preparation of 18F-labeled compounds (see e.g., Moon et al., Org. Biomol. Chem., 2011, 9, 8346-8355; and Kuik et al., J. Nucl. Med., 2015, 56, 106-112). To achieve high regioselectivity, arenes such as anisole and thiophene are often used as directing groups based on electronic discrimination, with the incoming [18F]fluoride intended for less electron-rich arenes (see e.g., Ross et al., J. Am. Chem. Soc., 2007, 129, 8018-8025). In the presence of a copper catalyst, the regioselectivity of diaryliodonium salts during radiofluorination can be controlled with high selectivity (see e.g., Ichiishi et al., Org. Lett., 2014, 16, 3224-3227).
Recently, spirocyclic iodonium ylides were described as arene radiofluorination precursors for hindered and non-activated substrates (see e.g., Rotstein et al., Nat. Commun., 2015, 5, 4365-4371). Iodonium ylides present several advantages for radiofluorination over diaryliodonium salts, foremost being the lack of a counterion and an auxiliary arene. As a result, iodonium ylides can be readily prepared and purified by flash chromatography and radiofluorination can be expected to proceed with high specific activity from [18F]fluoride with complete regioselectivity. Cardinale, et al., RSC Advances, 2014, 4(33), 17293-299 and U.S. Pat. Appl. Publ. Ser. No. 2015/0252007A1 iodonium ylides that can be used for fluorination, including radiofluorination of aromatic compounds.
While the utility of these precursors has been demonstrated for synthesis of radiopharmaceuticals (see e.g., Stephenson et al., J. Nuc. Med., 2015, 56, 489492) and bioconjugation reagents (see e.g. Want et al., Angew. Chem. Int. Ed., 2015, 54, 12777-12781; Jacobson et al., J. Nucl. Med., 2015, 56(11), 1780-5; and Calderwood et al., J. Fluor. Chem., 2015, 178, 249-253) the underlying characteristics of these radiofluorination reactions, including mechanism and auxiliary substitution effects, remained uncertain and represented a major hurdle to further advance these reactions in drug labeling and radiotracer development.